Recent research suggests that a variety of lifestyle - especially dietary - changes influencing the integrity of gastrointestinal function may be driving at least some portion of the increased prevalence of illnesses of civilization, including neuropsychiatric problems, such as autism, attention-deficit-hyperactivity disorder, major depression, obsessive-compulsive disorder and Alzheimer disease. One area of interest involves the relationship between the gut's microbiome (as well as the related functional integrity of the gastrointestinal tract) and mental health.

1. CNP
Oct.10,
2014.
Sinaia
Ede Frecska, Department of Psychiatry
University of Debrecen

2. Thatshouldbeyourgutflora

3. Yourmicrobiota

4. Question #3:
What are the two dumbest
species on Earth?
AmonkeywhichcallsitselfHomosapienssapiensanditsbestfriend
Canisfamiliaris.Theydon’tknowwhatisthebestforthemtoeat.

5. Our gut flora consists of
10-times more cells and
100-times more genes
than our body.
We are Petri dishes
on foot.
The forgotten organism
Meet Joe Brown

6. The human
superorganism
Human
cells
Microbiota
organisms
(virus, bacteria, fungi)
The human genome is in close relationship with
the microbiome
The microbiota is part of our phenotype
Microbiota
genom
(microbiome)
The total genome
of humans
Human
genome

7. The gut flora is part of the human microbiota
• 300-1000 species of
microorganisms
• in commensal and symbiotic
relationship with us
• with million years of
coevolution in behind
• influence almost every vital
processes inside us

8. Bourlioux P et al 2003, Am J Clin Nutr
Our cohabitants for life
Enteroecology or
biofascism?
Are there undesirable species
in a healthy gut?

9. In mutual codependence
The gut flora fulfills numerous functions:
– burns unused calories
– keeps the pH low
– suppresses pathogens
– trains the immune system
– regulates the development of gut and brain
– synthetizes vitamins (e.g., biotin and Vit. K)
– controls fat metabolism
– is the main source of kinurenic acid and SCFAs
(for gut mucosa, immune cells and neurons)
– repairs gut via Toll-like receptors

10. Goa'uld, the symbiote in the Stargate TV series
Stargate SG-1, 1997

11. The Tau'ri’s symbiote also kills cancer
Its immune function involves:
• cytokine activation, lymphatic stimulation
• tolerance against oral allergens
• immune-discrimination
• T-helper 17 cell differentiation which elicits
pTH17 response for antitumor environment
Chemotherapeutic agents like cyclophosphamide
and platinum work through the microbiota!1,2
1. Viaud S et al 2013, Science; 2. Iida N et al 2013, Science

12. The gut flora modulates the expression of numerous
critical genes: e.g., for BDNF, NMDA, and 5-HT
receptors. It communicates chemically with the striatum,
hippocampus, amygdala, hypothalamus, and cingulum.
The effects of gut flora on the CNS

13. Rodents with sterile intestines are anxious, more
sensitive to stress, and exhibit less exploratory activity.
The gut flora influences stress-reaction

14. The microbiota-gut-brain axis

15. The brain-immune-gut triangle (BIG-T)
– with microbiota in the center
gut-immune interaction
Szabo A et al 2013, Curr Immun Rev

16. Diet and gut flora
• The three major enterotypes of the gut flora
are quasi-selective in processing the three
major dietary components (carbohydrates,
fats, and proteins)
• Enterotypes are not dictated by age, gender,
body weight, or national divisions
• But their distribution is greatly influenced by
the distribution of the dietary components
• We have no other organ as much sensitive
to lifestyle changes!
1. Arumugam M. 2011, Nature; 2. Muegge BD. 2011, Science

17. Weapons of mass destruction
Western diet results in sub-optimal, dysbiotic pattern of the gut flora species

18. “Leaky gut”: the source of
degenerative and immune illnesses?
Increased permeability is a characteristic of the “civilized” gut,
with loose connections between gut cells.
Caused by:
proteotoxic effects of gluten and casein,
dysbiotic gut flora, grilling-frying, stress,
low fiber in food, too much physical exercise (“No sport!” – said
Sir Winston Churchill)
Aggravated by:
NSAID, aspirin, steroids, antacids (PPIs), antibiotics
Leading to:
chronic low-grade inflammation

19. 1. leaky gut → chronic low-grade inflammation:
A leaky gut lets some gut contents (endotoxins, LPSs) to enter
circulation and shifts the anti-inflammatory ↔ pro-inflammatory
cytokine balance to pro-inflammatory.
2. chronic low-grade inflammation → universal membrane
deficiency → illnesses of civilization:
The long-lasting pro-inflammatory condition can change the
permeability of other membranes in the body (e.g., blood-brain
barrier, synovial stratum, endothel, bronchial mucosa and
alveolar wall). This way the permeability problem of the gut
extends to other barriers, and a universal membrane deficiency
may be the common ground of many illnesses of civilization.
The gut and the GUT
(Grand Unification Theory) in medicine

20. The 3 degrees of gluten sensitivity

21. Comorbid conditions of “leaky gut”

22. According to the ’clearance’ hypothesis:
• The BBB is not just a barrier but a dynamic, two-way interface
between the blood and the CNS1
• The in-and-out transport of the soluble form of amyloid-β-peptid
(sABP) is regulated by ‘receptors for advanced glycation end
products’ (RAGE) and ‘low-density receptor-related protein-1’
(LRP1) complexes2
• Deficit in the outward transport of the sABP has a role in the
accumulation of amyloid plaques
• LPS induced inflammation facilitates the
retention of sABP within the CNS3
• BBB permeability is also increased by deficits of endothelial cells4
The blood-brain barrier in Alzheimer’s disease
1. Sharma HS et al 2012, Int Rev Neurobiol; 2. Deane R et al 2009, CNS
Neurol Disord Drug Targets; 3. Erickson ME et al 2012 J Neuroinflammation;
4. Bowman GL and Quinn JF 2012, Aging Health

23. The “leaky gut” and exorphins in ASD
A controversial study by the Royal Free Hospital
of London found more gastrointestinal problems in
autistic children (N=60) than in healthy controls.
90% of autistic children had chronic enteritis.1
Gliadomorphins and casomorphins originating
from poorly digested gluten and casein may enter
circulation, pass the BBB and exert endorphin-like
effects.2
Autistic children have dysbiotic gut flora.3
1. Wakefield AJ 2000, Am J Gastroenterol;
2. Shattock P 2002, Expert Opin Ther Targets;
3. Paraccho HM 2005, J Med Microbiol.

24. Curr Opin Psychiatry 2011, 24(6):519-525
Inflammatory mechanisms in major depressive disorder.
inflammation depression
BMC Medicine 2013, 11(200):1-16
So depression is an inflammatory disease,
but where does the inflammation come from?
poor diet
leaky gut
stress
obesity
atopy
Vitamin D
deficiency

25. • Cytokine activation by endotoxin infusion elicits typical
major depression (sickness behavior) in healthy subjects1
• Parenteral administration of cytokines may result in
affective, vegetative, behavioral, and cognitive symptoms
of depression (e.g., treatment of hepatitis C by interferon-
alpha causes depression in 25% of subjects)2,3
• Antidepressants (especially SSRIs), decrease plasma
level of pro-inflammatory cytokines (e.g., TNF-α, IL-1) and
increase anti-inflammatory cytokines (e.g., IL-10)4,5
• SSRIs also change the gene expression of the above
cytokines in the expected direction
Depression and inflammation
1. Reichenberg A et al 2001, Arch Gen Psychiatry; 2. Udina M et al 2012,
J Clin Psychiatry; 3. Connor TJ et al 1998, Life Sci; 4. Xia Z et al 1996,
Immunopharmacology; 5. Maes M et al 1999, Neuropsychopharmacology

26. depression ↓
Th2 (humoral)
IL-4, IL-5, IL-9,
IL-13 ↑
depression ↑
Th1 (cellular)
IL-2, IL-12, IFN-γ,
TNF-α ↑
Cytokines in depression
A dysbiotic gut flora shifts the balance to Th1

27. Stress
Depression
Leaky gut
Lysosomal
overload
LPS influx and
endotoxemia
Chronic, low-
grade
inflammation
Gut flora
Pro-
inflammatoric
cytokine balance

28. Good morning! to the gut flora
(an example of primate food for humans)
“Canopy-type smoothie” breakfast for 2 persons:
‒ 1 small apple with skin
‒ 1 small pear with skin
‒ 1 kivi with skin
‒ 1 banana without skin
‒ 2 salad leaves
‒ 2 white cabbage leaves
‒ 2 red cabbage leaves
‒ 2 napa cabbage leaves
‒ a couple of spinach leaves
‒ 1 big mushroom
‒ 1 spoonful of cinnamon
‒ small amount of nutmeg, clove and ginger
‒ 1/2 avocado or some virgin olive oil
‒ honey as sweetener
‒ 6 oz lemonade or hibiscus (Jamaica flower) tea
NO SOY, NO DAIRY. GLACIER MILK, EGG AND BUGS OK!